DESIGN & SYNTHESIS OF OLIGONUCLEOTIDE ANALOG ANTIVIRALS

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The goal of this research is to build oligonucleotide analogs (15-25 mers) complementary to key regulatory viral mRNAs or pre- mRNAs that will block translation and viral replication. The nucleoside units or the analogs are to be linked by substituted phosphonates constructed via organotransition metal reactions. In some instance the organometallic unit would be retained as part of the structure in order to enhance stability. The specific objectives of the project can be summarized as follows: 1) Find organotransition metal driven coupling processes leading from H-phosphonates or phosphites to phosphonates that proceed under the mild conditions in high yield. The reactions of organometallic intermediates derived from manganese, cobalt, palladium, and iron will be investigated. These will include reactions in which a metal phosphorus bond is formed between the transition metal and the alkyl phosphite, which may or may not subsequently rearrange to a metal phosphonate complex; reactions in which an alkyl phosphite is directed to a transition metal complexed ligand and as a result becomes attached to the metal via a spacer; reactions in which an alkyl phosphite combines with a transition metal complexed ligand, from which the metal is eliminated to give an alkyl or alkenyl phosphonate. 2) Determined what side-chain structural variations are compatible with the organometallic intermediates and the reagents necessary for oligonucleotide synthesis. 3) Build a series of oligodeoxyribonucleotide analogs with modified phosphonate linkages between nucleoside units. Side-chains attached to the phosphonates would be designed to enhance binding to complementary mRNA sequences through electrostatic interactions. 4) Test the antiviral activity, biological stability, transportability, and hybridization properties of synthetic oligodeoxyribonucleotide analogs.